Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/14—Ortho-condensed systems

Definitions

• This invention relates to new 1,1-disubstituted- l,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]quinolizinium salts, to processes for their preparation and to their use in the enantioselective synthesis of optically active 14-oxo-E-homo-eburnane derivatives of formula (Ia) wherein R represents a C 1-4 alkyl group.
• optically active compounds of general formula (Ia) are known in the art and may be used in the synthesis of (+)-vincamine and (+)-apovincaminic acid ethyl ester (Cavinton R ), which have celebral vasodilating activity.
• (+)-vincamine and (+)-apovincaminic acid ethyl ester there are numerous processes known in the art for the preparation of (+)-vincamine and (+)-apovincaminic acid ethyl ester [see e.g. JACS, 1540 (1979)]. In most of them one of the racemic intermediates is resolved and the desired antipode obtained is subjected to the subsequent synthesis steps. This resolution step, however, results in a loss of at least 50% in yield. It would therefore be desirable to provide an enantioselective synthesis for the production of (+)-vincamine and/or -apovincaminic acid ethyl ester which does not require such a resolution step.
• the resultant cholopentanoyltryptophan isopropyl ester was subjected to ring closure by means of phosphorus oxychloride in benzene and was then treated with a mild base in methylene chloride to yield the perchlorate of optically active ethyl 1-ethyl-hexahydroindoloquinol- izine-6-carboxylate of the general formula (II). Before the subsequent step of electrophilic alkylation with an acrylic acid ester derivative, however, the corresponding free base had to be liberated from the perchlorate. This treatment was carried out in methylene-chloride, with a 2% aqueous sodium hydroxide solution.
• a chiral indolo[2,3-a]quinolizinium salt may be alkylated in the presence of a catalytic amount of a strong base, preferably an alkali metal alcoholate, such as potassium tert.butylate without attacking the chiral centre present.
• a catalytic amount of strong bases during alkylation has been reported only in connection with non-chiral compounds [Tetrahedron 34, 3001-3004 (1978) and Hungarian Patent Application RI-713].
• the addition reaction may be accomplished by reacting a hexahydroindoloquinolizinium salt with a corresponding, reactive olephin, such as acrolein or methylenemalonic acid ester.
• the compounds of general formula (Ia) may be prepared by reacting an optically active 6-alkoxy-carbonyl-hexahydroindoloquinolizinium salt of formula (II), wherein
• optically active starting compounds of general formula (II) can be prepared by reacting an optically active tryptophan ester derivative with an alkylvaleric acid halide in the presence of an acid binding agent and subjecting the optically active halopentanoyltryptophan ester derivative obtained to simultaneous cyclisation and dehydration followed by treatment with a base.
• optically active starting compounds of general formula (II) contain a centre of chirality at the site of attachment of the carboxyl group. This centre of chirality preserves the optical activity of the the optically active tryptophan ester from which compound has been prepard until a new centre of chirality is formed in the molecule in a configuration corresponding to the desired end product. After this the carboxyl group which is not needed in the end product and only served to preserve the optical activity can be eliminated at any appropriate time. Although when the carboxyl group is eliminated, the centre of chirality at the carbon atom to which it has been attached ceases to exist, the molecule already has the desired optical activity.
• the reaction of the starting compounds of the general formula (II) with methylenemalonic acid diester derivatives of the general formula (III) can be completed in an unusually short time, i.e. in about half to one hour and consequently, the end product may be obtained in an optical purity exceeding 90%.
• Optical purity was determined in comparision with compounds of general formulae (Ia) and (VIII), which have a known absoulte opical rotation.
• the compounds of general formula (II) are conveniently reacted with the compounds of general formula (III) in an inert organic solvent such as, for example an aliphatic or aromatic hydrocarbon optionally substituted by one or more halogens, e.g. dichloromethane, dichloroethane, chloroform or chlorobenzene and preferably under anhydrous conditions.
• an inert organic solvent such as, for example an aliphatic or aromatic hydrocarbon optionally substituted by one or more halogens, e.g. dichloromethane, dichloroethane, chloroform or chlorobenzene and preferably under anhydrous conditions.
• the reaction is performed in the presence of a basic catalyst preferably an alkali metal tertiary alcoholate, most preferably potassium tert.-butylate.
• Convenient temperatures for the reaction are from 0 to 35°C, preferably 10 to 25°C.
• the acid hydrolysis of the compounds of general formula (IV) is generally accomplished with a dilute aqueous mineral acid, preferably with a mineral acid easy to eliminate when evaporating the reaction mixture, e.g. a dilute aqueous hydrochloric acid solution.
• the acid hydrolysis is conveniently performed at an elevated temperature, preferably about the boiling temperature of the reaction mixture (80 to 120°C).
• the alkaline hydrolysis is preferably carried out with an aqueous solution of an alkali metal hydroxide, most preferably sodium hydroxide.
• an alkali metal hydroxide most preferably sodium hydroxide.
• alkanols having 1 to 4 carbon atoms preferably ethanol can be employed. After eliminating the alkanols, the alkali metal salts obtained during the neutralisation following the hydrolysis are readily dissolved in the aqueous solution and accordingly do not contaminate the new, optically active compounds of general formula (V) obtained.
• Alkaline hydrolysis is preferably performed at room temperature (10 to 35°C).
• the selective . decarboxylation of the compounds of general formula (V) is generally carried out by heating, at a temperature of from 150°C to 200°C, preferably 165°C to 175°C, preferably in an inert organic solvent having a high boiling point.
• an inert organic solvent having a high boiling point any inert organic solvents having a boiling point of from 150°C to 200°C may be employed, e.g. decalin,.tetralin, quinoline or isoquinoline. Decalin is particularly preferred.
• the compounds of general formula (VI) may be saturated with catalytically activated hydrogen or a chemical reducing agent.
• catalytically activated hydrogen metals, e.g. palladium, platinum, nickel, iron, copper, cobalt, chromium, zinc, molybdenum, wolfram and their oxides may be employed as a hydrogenating catalyst.
• Catalytic hydrogenation may be carried out also in the presence of catalysts which have previously been precipitated on the surface of a carrier.
• Such carriers include carbon, preferably charcoal, silica, alumina and sulfates and carbonates of alkali earth metals.
• Catalytic hydrogenation is preferably accomplished in an inert solvent, such as water, aqueous alkaline solutions, alcohols, ethyl acetate, dioxan, glacial acetic acid, dimethylacetamide, dimethylformamide or mixtures thereof.
• an inert solvent such as water, aqueous alkaline solutions, alcohols, ethyl acetate, dioxan, glacial acetic acid, dimethylacetamide, dimethylformamide or mixtures thereof.
• complex metal hydrides e.g. borohydrides, such as alkali metal borohydrides, preferably sodium borohydride or aluminium hydrides such as lithium aluminium hydride can be employed.
• Chemical reduction is preferably performed in an inert solvent such as water, aqueous alcohol or acetonitrile.
• Preferred solvents or suspending agents include aliphatic alcohols, e.g. methanol.
• compounds of general formula (VI) are most preferably saturated by catalytic hydrogenation in the presence of a palladium-on-charcoal catalyst, in an inert organic solvent, such as dimethylformamide.
• a palladium-on-charcoal catalyst in an inert organic solvent, such as dimethylformamide.
• an epimeric mixture of compounds of general formula (VII) is obtained, containing the cis isomer in an overwhelming majority.
• C/D cis annelated la-alkyl-12aH-octahydro-indoloquino- lizines are obtained stereoselectively and the corresponding trans 12b&H-epimers are obtained only as byproducts.
• the two epimers of general formula (VII) can be separated, but their separation is not required for the subsequent step of synthesis.
• Cyclisation of the compounds of general formula (VII) may be carried out, for example, with a phosphorus halide, phosphorus oxyhalide or sulfur oxyhalide, such as e.g. phosphorus pentachloride, phosphorus pentabromide or thionyl chloride. Phosphorus oxychloride is particularly preferred.
• the reaction temperature is generally from 10°C to 100°C, preferably 15°C to 30°C.
• the cyclisation may also be performed at a temperature of 60 to.80°C for one to 3 hours.
• the process according to the invention is preferably carried out by subjecting the cis-trans mixture of the compounds of general formula (VII), obtained by saturating compounds of general formula (VI) to cyclisation without isolation from the reaction mixture, thereby reducing the reaction steps of the overall synthesis.
• the total yield calculated for the starting compounds of general formula (II) amounts to about 35%.
• the optical purity of the compounds of general formula (Ia) obtained is about 96%.
• the major product of the cyclisation is the compound of formula (Ia). However a few percent of a cis-trans isomeric mixture of general formula (Ib) may also be isolated as a by-product from the mother liquor.
• the acids of general formula (VI) may first be converted into their corresponding esters of formula (VIa) which are then saturated, or alternatively, they are saturated and then the acids of general formula (VII) obtained are converted into the corresponding esters.
• routes octahydro- indoloquinolizine ester derivatives of general formula (VIII) are obtained, which may then be cyclized in a known manner, for example by means of sodium ter.- butylate (Hungarian Patent Specification No. 163,769).
• the esterification of the compounds of general formula (VI) and (VII), respectively may be carried out as described in British Patent Specification No.
• the new enantioselective synthesis for the preparation of the compounds of general formula (Ia), which are useful intermediates in the preparation of pharmaceutically active alkaloids having an eburnane skeleton, provides the desired products with a very good yield, in a high optical purity.
• the reactions involved are very easy to carry out.
• a further advantage of the process according to the invention lies in the fact that, by using the extremely reactive compounds of general formula (III), racemisation is practically impossible.
• dicarboxylic acids of the general formula (V) can be prepared, from which the functional carboxyl group preserving the original chirality can be eliminated by selective decarboxylation, without any difficulty.
• the compounds obtained can directly be transformed into the desired compounds of the general formula (Ia), and the conversion can be performed with an excellent yield, giving the compounds of the general formula (Ia) in a high optical purity.
• the catalyst When the calculated amount of hydrogen has been taken up, the catalyst is filtered off, washed with two 5-ml. portions of dimethylformamide and the combined organic phases are evaporated to dryness under a pressure of 1 to 2 mmHg.
• the mixture is separated into three components by preparative thin layer chromatography (KG-PF 254+366' a 140:30 mixture of benzene and methanol, elution: acetone).
• the substance having the lowest R f -value weighs 240 mg.
• optical rotatory powers correspond to the free base.
• (+)-14-oxo-E-homoeburnane are obtained as an oily product which can be easily isolated.
• the R f -values decrease in the following order: (+)-14-oxo-3-epi-E-homo-eburnane > (+)-14-oxo-E-homo-eburnane > (-)-1 ⁇ -ethyl-1 ⁇ -methoxycarbonylethyl-1,2,3,4,6,7, 12,12b-octahydro-indolo[2,3-a]quinolizine (KG-G, a 14:3 mixture of benzene and methanol).
• the catalyst When the calculated amount of hydrogen is taken up, the catalyst is filtered off from the reaction mixture. The catalyst is then washed with two 5- ml. portions of dimethylformamide and the combined organic phases are evaporated to dryness on a bath of 50 to 60°C, under a pressure of 1 to 2 mmHg.
• the oily residue is dissolved in 3 ml. of phosphorus oxychloride under cooling with ice and the solution is kept at room temperature for two or three days.
• optical purity was determined on (-)-la ethyl-la-methoxycarbonylethyl-1,2,3,4,6,7,12,12ba- octahydro-indolo[2,3,a]quinolizine prepared by opening the lactam ring of (+)-14-oxo-E-homo-eburnane (3a,17a) as described below:
• the reaction mixture is treated with 1 to 2 drops of acetic acid under cooling with ice and the solvent is eliminated in vacuo.
• the residue is dissolved in 2 ml. of dichloromethane, the pH of the solution is adjusted to 9 with 1 ml. of a 5 % aqueous sodium carbonate solution, the organic phase is separated and the extraction is repeated with a further 2-ml. portion of dichloromethane.
• the organic phases are combined, dried over anhydrous magnesium sulfate, filtered and the solvent is distilled off from the filtrated in vacuo. As a distillation residue 58 mg.
• the chromatographically isolated product having a higher R f -value weighs 41 mg. (14.1%) and is identified as (+)-la-14-oxo-3-epi-E-homo-eburnane.
• the oily product weighing 41 mg. is crystallised from 0.3 ml. of methanol to yield 31 mg. of crystalline (+)-14-oxo-3-epi-E-homo-eburnane, melting at 110 to 112°C (ethanol). [The melting point of this product according to Hungarian Patent Application No. 781/80 is 121 to 122°C (isopropanol)].
• optical purity is determined on (-)-la- ethyl-1 ⁇ -methoxycarbonylethyl-1,2,3,4,6,7,12,12b ⁇ -octahydro-indolo[2,3-a]quinolizine prepared by opening the lactam ring of (+)-14-oxo-E-homo-eburnane(3a,17a), as described in Example 5.
• optical rotatory power of (-)-la-ethyl-1 ⁇ -methoxy-carbonylethyl-1,2,3,4,6,7,12,12ba-octahydro- indolo[2,3-a]quinolizine is:

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Indole Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1980
  • 1980-10-17 HU HU802525A patent/HU183234B/hu not_active IP Right Cessation
• 1981
  • 1981-10-16 DE DE8181304833T patent/DE3165576D1/de not_active Expired
  • 1981-10-16 US US06/312,128 patent/US4399069A/en not_active Expired - Fee Related
  • 1981-10-16 JP JP56165543A patent/JPS57145876A/ja active Granted
  • 1981-10-16 EP EP81304833A patent/EP0050492B1/de not_active Expired

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